The present invention relates to a new injectable formulation of ramoplanin or a compound of the ramoplanin family. More particularly, the injectable formulations of the invention are particularly suitable for intravenous (i.v.) administration.
Ramoplanin (INN) is a known member of the cyclic peptide antibiotics more precisely known as glycolipodepsipeptides which has been described in U.S. Pat. No. 4,303,646 and U.S. Pat. No. 4,328,316. Originally it has been named antibiotic A 16686. It is a complex substance whose separate factors A1, A2 and A3 have been described in U.S. Pat. No. 4,427,656.
Ramoplanin factors Axe2x80x21, Axe2x80x22 and Axe2x80x23 have been described in EP-B-318680, the aglycones of any of the above factors have been described in U.S. Pat. No. 5,491,128 while the tetrahydrogenated derivatives of any of the above factors have been described in U.S. Pat. No. 5,108,988. A method for selectively increasing the ratio of single major components A2 A3 is described in EP 0259780. All the above mentioned patents are incorporated herein by reference.
The structure of ramoplanin and its factors and derivatives have been described in several articles and publications, see R. Ciabatti et al., J. Antib. 1989, 254-267, J. K. Kettenring et al., J. Antob 1989, 268-275, R. Ciabatti and B. Cavalleri, Bioactive Metabolites from Microorganisms, Elsevier Science Publishers, 1989, 205-219 and M. Kurz and W. Guba, Biochemistry 1996, 35, 12570-124575.
Rxe2x80x2 represents alpha-D-mannopyranosyl or s-o-alpha-D-mannopyranosyl-alpha-D-mannopyranosyl.
N. J. Skelton et al. in J. Am. Chem. Soc. 1991, 113, 7522-7530 describe another member of this family, which they call Ramoplanose.
These compounds can be represented by the following formula (Formula I): 
wherein:
R represents xe2x80x94COxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH3,
xe2x80x94COxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH (CH3)2,
xe2x80x94COxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH (CH3)2,
xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH3,
xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH (CH3)2 or
xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH (CH3)2 
Rxe2x80x2 represents alpha-D-mannopyranosyl or 2-O-alpha-D-mannopyranosyl-alpha-D-mannopyranosil,
or
Rxe2x80x2 represents 2,3-O-di[alpha-D-mannopyranosyl]-D-mannopyranosyl when R represents xe2x80x94COxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH(CH3)2,
a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof in any proportion.
The configuration of the double bonds of the unsaturated moieties reported above in the definition of R have been found to be 2 (E) or cis and 4 (Z) or trans in the literature reported above.
The following table specifies the meanings for R and Rxe2x80x2 of the single factors or derivatives with reference to the above formula:
The aglycones correspond to the compounds reported above wherein Rxe2x80x2 represents hydrogen while the tetrahydrogenate derivatives correspond to the compounds reported above wherein the mojety R is fully hydrogenated.
Ramoplanose is reported to correspond to xe2x80x9cfactor A2xe2x80x9d wherein Rxe2x80x2 represents 2,3-O-di[alpha-D-mannopyranosyl]-D-mannopyranosyl.
In the following description and claims, the term xe2x80x9cramoplaninxe2x80x9d refer to a ramoplanin complex wherein factor A2 is the major component, with a small amounts of factors Axe2x80x22, A1, Axe2x80x21, A3, Axe2x80x23 and other related substances accounting for the remainder of this active ingredient.
Particularly preferred is xe2x80x9cramoplaninxe2x80x9d wherein factor A2 represents at least, 75% of the active ingredient.
xe2x80x9cA member of the ramoplanin familyxe2x80x9d refers to any of the compounds reported above that are represented by Formula I, any salt or any mixture thereof in any proportion.
Ramoplanin as well as any members of the ramoplanin family are unsuitable for i.v. administration because of drawbacks such as swelling and progressive necrotization at the site of injection, and haemolysis as revealed by urine discoloration.
The formulations of the invention contain ramoplanin or a member of the ramoplanin family in admixture with a fat emulsion product for intravenous administration.
In general, for i.v. administration purposes according to this invention, it is suitable to utilize liquid compositions wherein ramoplanin or a member of ramoplanin family is present in concentration from 1 to 20 mg/ml, preferably, from 1.5 to 15 mg/ml, most preferably, from about 3 to about 5 mg/ml.
In the current description and claims the expressions xe2x80x9cfat emulsion product for intravenous injectionxe2x80x9d or xe2x80x9cfat emulsion productxe2x80x9d identify any of those fat emulsion products suitable for intravenous administration via a peripheral vein or by a central venous infusion that are currently used mainly to assure calories intake when parenteral nutrition is required. Examples of these substances are for instance reported in US Pharmacopeia, Martindale, The Extra Pharmacopeia (31st edition, 1996, page 1377) or VIDAL 1996, page 814. The above expressions include also those emulsions used as colloidal drug carriers, examples of which are reported in the book xe2x80x9cSubmicron Emulsions in Drug Targeting and Deliveryxe2x80x9d edited by S. Benita, Horwood Academic Publishers, 1998, at pages 119-122. All above cited publications are incorpored hereby by reference.
The above said fat emulsion products are largely based on an oil phase stabilized by emulsifiers, like phospholipids, poloxamers or other polyoxyethylene derivatives such as, for instance, polysorbates or polyoxyethylene castor oil.
Typically, a fat emulsion product suitable for preparing a formulation of the invention comprises an oil phase (usually 2-40%, preferably, 5-25% weight/vol), preferably consisting of vegetable oils such as soybean oil, safflower oil and cottonseed oil, emulsifiers (usually 0.2-5%, preferably, 0.5-2% weight/vol), preferably based on phospholipids of egg source such as egg lecithin or soybean lecithin, and additives as osmotic agents such as glycerol, sorbitol and xylitol.
These fat emulsion products, as commercially available, are emulsions comprising the above mentioned oil phase, emulsifiers and additives dispersed in water for injection and the oil phase is generally present in the emulsion in a percentage (weight/vol) of 5 to 25%. For preparing the i.v. administrable formulation of this invention, the fat emulsion product may be used as such or diluted with saline or water for injection added with an osmotic agent (eg. glucose) to decrease the oil phase concentration to a lower value and, at the same time, maintaining the desired osmolarity.
In general, if the concentration of ramoplanin or a member of ramoplanin family in the formulation is low, it is possible to lower the percentage of the oil phase in said i.v. formulation.
For instance, with ramoplanin concentrations of about 10 mg/ml, the percentage of the oil phase in the i.v. formulations of the invention may range between 4 to 40% (weight/vol) although are preferred those i.v. fat emulsions wherein the oil phase is between 4 and 25%, and, more preferably, between 8 and 18%, with the range 8-10% being currently the most preferred concentration.
With ramoplanin concentrations of about 1 mg/m the percentage of the oil phase in the i.v. formulation can be lowered to a range between 0.2 and 10% (weight/vol).
Generally, the osmolarity of the final i.v. formulation is between 250 and 300 mOsm/L, while the value of the pH must be compatible with the stability of ramoplanin (or a member of the ramoplanin family), and, therefore, usually, it should not be higher than 8.
As known in the art, particle size of the emulsion needs to be controlled for a proper i.v. administration, and this is accomplished through the conventional preparation and final formulation procedures.
Examples of fat emulsion products that can be conveniently used according to the present invention are those listed at page 120 of the above cited book: xe2x80x9cSubmicron Emulsion in Drug Targeting and Deliveryxe2x80x9d where the oil phase consists of soybean oil, cottonseed oil, safflower oil or mixture thereof.
Soybean oil, cottonseed oil and safflower oil contain long chain fatty acids comprising mainly linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid, essentially in the form of triglycerides.
Soybean oil, cottonseed oil and safflower oil can be totally or in part substituted by any mixtures of the above fatty acids in the form of triglycerides having a percent (weight/weight) composition substantially similar to that of the above oils or their mixtures. Moreover, part of the above mentioned vegetable oils or long chain fatty acids triglycerides may be substituted by medium chain (C6-C12) triglycerides.
Typically, the fat emulsion product used for the preparation of the i.v. formulations of this invention contains an oil phase in a range from 2 to 40 percent (weight/vol), preferably, from 5 to 25 percent, more preferably from 7 to 20 percent, emulsifiers) in a range from 0.2 to 5 percent (weight/vol), preferably, from 0.6 to 2 percent more preferably from 0.5 to 1.5 percent, and the additive is in an amount suitable to control osmolarity, preferably, in a range from 1.5 to 5 percent (weight/vol), more preferably preferably from 2 to 3 percent.
In said oil phase consisting of soybean oil, cottonseed oil or safflower oil or mixture thereof, or in the fatty acids mixtures which may substitute totally or in part the above oils, the fatty acids triglycerides are usually present in the following percent (weight/weight) proportion indicated between brackets: linoleic acid (40-70%), oleic acid (15-30%), palmitic acid (5-15%), linolenic acid (3-12%), stearic acid (2-6%).
As indicated above, for the preparation of the i.v. formulations of this invention, the above said fat emulsion products are used as such or are diluted in a isoosmotic water solution for injection to a concentration of the oil phase in the final composition that is at least 0.2% (weight/vol), normally, depending on the concentration of ramoplain or a member of ramoplanin family which is present in the final composition.
According to a preferred embodiment of this invention, those fat emulsion products that are currently available under the trade names Intralipid(copyright), Liposyn(copyright) and Lipofundin(copyright) may be utilized. For instance, Intralipid(copyright) (Kabi Vitrum/Pharmacia) and Liposyn(copyright) II and Liposyn(copyright) III (Abbott), have composition and physico-chemical properties as reported below:
As stated above, in the formulations according to this invention ramoplanin or a member of the ramoplanin family as defined above is generally present in the compositions of the invention in an amount of 1 to 20 mg/ml, with a range of 1.5 to 15 mg/ml being currently preferred, and a range from about 3 to about 5 mg/ml being the most preferred one.
Typically, the composition of the invention is a composition wherein the oil phase in the final fat emulsion is between 0.2 and 40% (weight/vol), with a range 4-25% being preferred, a range 8-18% being more preferred and with the range 8-10% being currently most preferred. However, as mentioned above, the proportion of the oil phase may be adjusted to the one of the antibiotic and to lower amounts of ramoplanin may correspond lower amounts of oil phase in the composition